Magnetic resonance imaging using hyperpolarized noble gases

ABSTRACT

A method of imaging a spatial distribution of a noble gas by nuclear magnetic resonance spectrometry includes detecting a spatial distribution of at least one noble gas by NMR spectrometry and generating a representation of said spatial distribution of the noble gas. The noble gas is selected from noble gas isotopes having nuclear spin, preferably Xenon-129 and/or Helium-3. The noble gas is at least thermally or equilibrium polarized and is preferably hyperpolarized, most preferably hyperpolarized by optical (laser) pumping in the presence of an alkali metal or by metastability exchange. The generation of the representation of the noble gas spatial distribution includes at least one dimension, preferably 2 or 3 dimensions of the spatial distribution. The noble gas may be imaged according to the invention in chemical or biological systems, preferably in a human or animal subject or organ system or tissue thereof. Also, apparatus for nuclear magnetic resonance imaging of the spatial distribution of at least one noble gas includes means for imaging a noble gas by NMR spectrometry and means for providing and/or storing imageable quantities of a noble gas, preferably hyperpolarized Xenon-129 and/or Helium-3. Also, a medical composition includes a medically acceptable bifunctional gas effective for in vivo anesthesiological and NMR imaging functions, including at least one noble gas, preferably hyperpolarized Xenon-129 and/or Helium-3.

BACKGROUND OF THE INVENTION

[0001] The present invention relates generally to techniques of nuclearmagnetic resonance imaging. In particular, the present invention relatesto, among other things, the detection and imaging of a noble gas bynuclear magnetic resonance spectrometry.

[0002] Current views as to the molecular basis of anesthetic action aremostly derived from experimental work carried out in vitro.Interpretation of many of the results of these studies are extremelycontroversial, e.g., changes in lipid structure are observed atexceedingly high, indeed toxic, concentrations of anesthetic. Changesobserved in vitro, from animals whose physiology has been altered, orfrom animals administered non-clinical doses of anesthetics might notreflect the effects of these agents clinically. It is believed thatsignificant progress can be made by employing direct non-invasivemethods for the detection and characterization of anesthetics in livinganimals. Both lipid solubility and protein binding undoubtedly do play arole, but new ideas are now needed.

[0003] Attempts have been made to bring powerful nuclear magneticresonance (NMR) techniques to bear on this problem. (References 1-3).Wyrwicz and co-workers pioneered the use of fluorine-19 (¹⁹F) NMRspectroscopy to observe fluorinated anesthetics in intact tissues andrecorded the first ¹⁹F NMR spectra from the brain of a live anesthetizedrabbit. (References 1, 4). These early studies demonstrated thefeasibility of studying the fate of anesthetics in live mammals. Burtand collaborators also used halothane and other fluorinated anestheticsfor monitoring membrane alterations in tumors by ¹⁹F NMR. (References5-6). In recent years, several groups have conducted ¹⁹F NMR studieswhich have shed light on the molecular environment of anesthetics in thebrains of rabbits and rats. (References 3, 7). Using a surface coilplaced on top of the calvarium during halothane inhalation, twooverlapping spectral features observed by d'Avignon and coworkers,perhaps 0.1-0.2 ppm apart, could be resolved through their differenttransverse relaxation times (T₂). (Reference 3). The biexponentialdependence of the spin-echo amplitude on echo delay reported in thisstudy demonstrated that anesthetics in different molecular environmentscould be discerned in the brain in vivo using ¹⁹F NMR. Suchenvironments, separated by chemical shifts of only about 0.1 ppm, hadpreviously been reported by Wyrwicz et al. in high resolution studies ofexcised neural tissue. (Reference 4).

[0004] Notwithstanding such attempts to use other compounds for NMRimaging, state-of-the-art biological magnetic resonance imaging (MRI)has remained largely restricted to the water proton, ¹H₂O, NMR signal.The natural abundance of water protons, about 80-100 M in tissue, andits large magnetic moment make it ideal for most imaging applications.Despite its tremendous value as a medical diagnostic tool, however,proton MRI does suffer several limitations. Most notably, the waterprotons in lung tissue, and the protons in lipids of all interestingbiological membranes, are notoriously NMR invisible as a result of theshort T₂ in such environments. (References 8-9). Other ¹H signals andsignals from other biologically interesting nuclides are either presentin too low a concentration (10⁻³ to 10⁻¹ M, compared to ca. 100 M forH₂O) or have undesirable NMR characteristics. In studying dynamicprocesses with ¹H₂O, one must sacrifice much of the proton signal toexploit differences in effective spin density resulting from T₁ and/orT₂ spatial variation. (Reference 10).

[0005] Various noble gases are known to be effective anesthetic agents.For example, Xenon is approved for use in humans, and its efficacy as ageneral anesthetic has been shown. Attempts have previously been made totake advantage of the properties of Xenon for purposes of medicalimaging, but success has heretofore been extremely limited, andtechniques have been impractical at best. For example, the ¹²⁷Xe isotopewas used in early ventilation studies of the lung. (References 11-12).Unfortunately, the poor image quality attained limited its clinical use.Xenon has, however, been used as a contrast enhancement agent incomputed tomography (CT) studies of the brain, (References 13-14), andas a tracer for regional cerebral blood flow (rCBF) measurements.(Reference 15).

[0006] An isotope of Xenon, Xenon-129 (¹²⁹Xe), has non-zero nuclear spin(i.e., ½) and therefore is a nucleus which, in principle, is suited tostudy by nuclear magnetic resonance techniques. Despite the apparentpotential for use of Xenon in magnetic resonance imaging, its smallmagnetic moment, and the low number densities of gas generallyachievable, have heretofore been insuperable obstacles to practicablemagnetic resonance (MR) imaging of ¹²⁹Xe at normal, equilibrium (alsoknown as “Boltzmann”) polarizations, P (P˜10⁻⁵ in 0.5-1.5 Tesla (T)clinical imaging systems). However, unlike the water proton (¹H)employed as the nucleus in conventional NMR techniques, the nuclearmagnetic resonance signals obtainable from ¹²⁹Xe are extraordinarilysensitive to local environment and therefore very specific toenvironment.

[0007] Certain aspects of the behavior of ¹²⁹Xe, and other noble gasisotopes having nuclear spin, in various environments have been studiedand described. For example, Albert et al. have studied the chemicalshift and transverse and longitudinal relaxation times of Boltzmannpolarized ¹²⁹Xe in several chemical solutions. (Reference 16). Albert etal. and others have also shown that oxygen can affect longitudinalrelaxation time T₁ of ¹²⁹Xe. (References 17-18). Miller et al. have alsostudied the chemical shifts of ¹²⁹Xe and ¹³¹Xe in solvents, proteins,and membranes. (Reference 2). However, none of these publicationsprovides any indication of a method by which ¹²⁹Xe could be used fornuclear magnetic resonance imaging.

[0008] It is known in the art that the polarization of certain nuclei,such as noble gas nuclei having nuclear spin, may be enhanced over theequilibrium or Boltzmann polarization, i.e., hyperpolarized. Suchtechniques include spin exchange with an optically pumped alkali metalvapor and metastability exchange.

[0009] The physical principles underlying the hyperpolarization of noblegases have been studied. (Reference 19). For example, Happer et al. havestudied the physics of spin exchange between noble gas atoms, such asXenon, with alkali metals, such as Rubidium. (Reference 20). Others havestudied spin exchange between Helium and alkali metals. (References21-22, 49). Other publications have described physical aspects of spinexchange between alkali metals and noble gases. (References 23-24). Thetechnique of using metastability exchange to hyperpolarize noble gaseshas been studied by Schearer et al. and by Hadeishi et al. (References26-31).

[0010] Other publications, by Cates et al. and Gatzke et al., describecertain behaviors of frozen, crystalline ¹²⁹Xe that has beenhyperpolarized. (References 32-33). Cates et al. and others describespin-exchange rates between Rubidium and ¹²⁹Xe at high Xenon pressuresas measured by magnetic resonance apparatus. (References 34-35). Thesepublications, however, relate to ¹²⁹Xe behavior in highly controlledphysical systems and provide no description concerning how ¹²⁹Xe mightbe used to produce images by nuclear magnetic resonance.

[0011] Raftery et al. have described optically pumped ¹²⁹Xe as anadsorption probe for the study of surface structure by analysis of NMRspectra. (References 36-37). Long et al. have also observed the chemicalshift of laser polarized Xenon adsorbed to a polymer surface. (Reference38).

[0012] U.S. Pat. Nos. 4,856,511 and 4,775,522 to Clark describe anuclear magnetic resonance technique for detecting certain dissolvedgases in an animal subject. Gas compositions described as useful forthis technique include fluorine compounds such as perfluorocarbons.Other gases suggested to be potentially useful for the technique ofClark include ¹²⁹Xe, but Clark fails to recognize any of thedifficulties which have heretofore rendered use of ¹²⁹Xe for magneticresonance imaging of biological subjects impracticable.

[0013] Therefore, it would be a significant advance in the art toovercome the above-described difficulties and disadvantages associatedwith nuclear magnetic resonance imaging, in a manner which would permitthe imaging of noble gases, especially the imaging of noble gases inbiological systems, without requiring excessively long image acquisitiontimes and without being limited to systems and environments previouslyimageable only by ¹H NMR.

SUMMARY OF THE INVENTION

[0014] In accordance with the present invention, there is provided amethod of performing nuclear magnetic resonance imaging which includesdetecting the spatial distribution of at least one noble gas by nuclearmagnetic resonance (NMR), and generating a representation of the noblegas spatial distribution.

[0015] In a preferred embodiment, there is also provided a method ofperforming nuclear magnetic resonance imaging of an animal or humansubject by administering an imageable amount of at least one noble gasto the subject, employing an NMR imaging spectrometer to detectradio-frequency signals derived from the magnetic resonance of at leastone noble gas, processing the detected signals to obtain an NMRparameter data set as a function of the spatial distribution of at leastone noble gas, and further processing the data set to generate arepresentation of at least one dimension of the spatial distribution ofat least one noble gas.

[0016] In another preferred embodiment, the method of the inventionfurther includes detecting and imaging at least one hyperpolarized noblegas. The hyperpolarized noble gas is preferably hyperpolarized by laserpolarization through spin exchange with an alkali metal or bymetastability exchange. The noble gas is preferably selected from amongHelium-3, Neon-21, Krypton-83, Xenon-129, Xenon-131 and mixturesthereof. Most preferably, the noble gas is Helium-3 or Xenon-129.Combinations of noble gases and/or noble gas isotopes are contemplated,as are combinations of hyperpolarized and non-hyperpolarized noble gasesand/or noble gas isotopes. When the noble gas is laser polarized throughspin exchange with an alkali metal, preferably an alkali metal selectedfrom among Sodium-23, Potassium-39, Cesium-133, Rubidium-85, andRubidium-87. Most preferably, the alkali metal is Rubidium-85 orRubidium-87.

[0017] The method of the invention preferably includes detecting andimaging at least one physical dimension of the spatial distribution ofat least one noble gas, more preferably including detecting and imagingtwo or three physical dimensions. The method of the invention may alsoinclude detecting and imaging alterations of the spatial distribution ofthe noble gas as a function of time.

[0018] The generating of a representation of a noble gas preferablyincludes generating a representation of at least one physical dimensionof the spatial distribution of the noble gas, more preferably includinggenerating a representation of two or three physical dimensions of thenoble gas. The generating of the representation may also includegenerating a representation of one or more physical dimensions of thespatial distribution of the noble gas as a function of time, includingsuch NMR parameters as chemical shift, T₁ relaxation, T₂ relaxation, andT_(1ρ)relaxation. Preferably, the method of the invention includesgenerating a visual representation.

[0019] The noble gas being imaged is preferably distributed spatially inat least one physical phase such as a gas, liquid, gel, or solid. Thenoble gas may be imaged as distributed in two or more physical phases inone sample. The noble gas being imaged may be distributed on a solidsurface. The noble gas may be imaged in association with variousmaterials or environments.

[0020] The sample being imaged using a noble gas may include an in vitrochemical, in vitro biological or in vivo biological, system. When thenoble gas distribution in an in vivo biological system is imaged, thesystem may include one or more human or animal subjects. The noble gasis preferably distributed in an organ or body system of the human oranimal subject. Alternatively, the noble gas may be distributed in ananatomical space of the subject.

[0021] In another embodiment of the invention, there is provided amedical composition which includes a medically acceptable bifunctionalgas effective for in vivo anesthesiological and nuclear magneticresonance imaging functions. In a preferred embodiment, the gascomposition includes at least one noble gas, preferably selected fromamong Helium-3, Neon-21, Krypton-83, Xenon-129, and Xenon-131. Morepreferably, the noble gas is Helium-3 or Xenon-129. The noble gas ispreferably hyperpolarized, more preferably through spin exchange with analkali metal or through metastability exchange. Combinations ofhyperpolarized and non-hyperpolarized noble gases and noble gas isotopesare possible.

[0022] Also in accordance with the present invention, there is providedapparatus for nuclear magnetic resonance imaging which includes NMRimaging means, for detecting and imaging at least one noble gas, andmeans for providing imageable quantities of the noble gas. In apreferred embodiment, the apparatus includes means for providingimageable quantities of a hyperpolarized noble gas. The apparatus ofthis embodiment includes hyperpolarizing means, preferably means forhyperpolarizing a noble gas through spin exchange with an alkali metalor through metastability exchange. The noble gas may be provided incontinuous, discontinuous, and/or quasi-continuous mode, and when morethan one noble gas is provided, noble gases may be provided as a mixtureor individually, and may be provided either together or by separateroutes and/or at separate times and durations.

[0023] The noble gas may be contacted with the sample to be imaged ingaseous, liquid, or solid form, either alone or in combination with oneor more other components in a gaseous, liquid, or solid composition. Thenoble gas may be combined with other noble gases and/or other inert oractive components. The noble gas may be delivered as one or more bolusesor by continuous or quasi-continuous delivery.

[0024] Also in accordance with the invention there is provided a methodof performing nuclear magnetic resonance imaging of a human or animalsubject. In this embodiment, the method includes administering to asubject an imageable amount of a hyperpolarized noble gas, generatingradio-frequency signals from the nuclear magnetic resonance of thehyperpolarized noble gas by means of a nuclear magnetic resonanceimaging spectrometer, detecting the generated radio-frequency signals,processing the detected radio-frequency signals to derive a nuclearmagnetic resonance parameter data set as a function of a spatialdistribution of the hyperpolarized noble gas in the subject, and furtherprocessing said nuclear magnetic resonance parameter data set to derivea representation corresponding to at least one spatial dimension of thespatial distribution of the hyperpolarized noble gas in the subject.

[0025] The noble gas may be administered to a human or animal subject asa gas or in a liquid, either alone or in combination with other noblegases and/or other inert or active components. The noble gas may beadministered as a gas by either passive or active inhalation or bydirect injection into an anatomical space such as lung orgastrointestinal tract. The noble gas may be administered as a liquid byenteral or parenteral injection. The preferred method of parenteraladministration includes intravenous administration, optionally bycontacting blood with the noble gas extracorporeally and reintroducingthe noble gas-contacted blood by intravenous means.

[0026] The present invention solves the disadvantages inherent in theprior art by providing a method for imaging at least one noble gas bynuclear magnetic resonance. The present method provides a new andunexpectedly powerful method of NMR imaging of noble gas spatial andtemporal distribution in non-biological as well as in in vitro and invivo biological systems. The present invention also permits theacquisition of images of high signal to noise ratio, in unexpectedlyshort acquisition periods. In addition, the present invention provides amethod for imaging biological phenomena of short duration as well as forimaging systems previously not amenable to imaging by conventional ¹HNMR techniques.

[0027] Other objects and advantages of the present invention will becomemore fully apparent from the following disclosure, figures, and appendedclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028]FIG. 1a shows a nuclear magnetic resonance spectrum of ¹²⁹Xe in arat brain synaptosome suspension; FIG. 1b shows a nuclear magneticresonance spectrum of ¹²⁹Xe in a homogenate of rat brain tissue; FIG. 1cshows a nuclear magnetic resonance spectrum of ¹²⁹Xe in a whole ratbrain preparation.

[0029]FIG. 2a shows a graphical representation of a glass sphere 20 mmin diameter; and FIG. 2b shows a nuclear magnetic resonance image ofBoltzmann polarized ¹²⁹Xe gas in a 20 mm diameter glass sphere.

[0030]FIG. 3a shows a graphical representation of a glass sphere, 20 mmin diameter, containing octanol (shaded region) and Xenon gas (unshadedregion); FIG. 3b shows a nuclear magnetic resonance spectrumillustrating NMR signals obtained from ¹²⁹Xe in gas phase and inoctanol; FIG. 3c shows a nuclear magnetic resonance image of ¹²⁹Xe inoctanol in 20 mm glass sphere; and FIG. 3d shows a nuclear magneticresonance image of ¹²⁹Xe in gas phase in a 20 mm glass sphere.

[0031]FIG. 4 shows a series of nuclear magnetic resonance images of ahyperpolarized ¹²⁹Xe gas phantom, representing different mutuallyparallel planes.

[0032]FIGS. 5a-5 c show a sequence of nuclear magnetic resonance imagesof a mouse lung inflated with hyperpolarized ¹²⁹Xe gas; and FIG. 5dshows a nuclear magnetic resonance image of ¹H in a mouse heart.

[0033]FIG. 6 shows a graph illustrating a decrease in ¹²⁹Xe magneticresonance signal intensity, obtained from mouse lung inflated byhyperpolarized ¹²⁹Xe, as a function of time.

[0034]FIG. 7 shows a longitudinal section view of a noble gas deliverydevice for nuclear magnetic resonance imaging of noble gases.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Nuclear magnetic resonance spectroscopy is a technique which iswell known in a wide variety of scientific disciplines. Basicconsiderations regarding the conventional practice of nuclear magneticresonance imaging, especially as applied to biological systems, arefound in Rinck et al., An Introduction to Magnetic Resonance in Medicine(1990), especially Chapters 1-4 (Reference 39); and Wehrli, F. W.,“Principles of Magnetic Resonance”, Chapter 1, and Wood, M. L., “FourierImaging”, Chapter 2, in Magnetic Resonance Imaging, Vol. 1, 2d ed.,Stark et al., eds. (1992) (Reference 40). These publications areincorporated by reference herein. In certain disciplines, an adaptationof NMR spectroscopy, involving the generation of images from NMR datahas found increasing popularity. In medicine, certain MRI techniqueshave become fairly commonplace, principally employing the water proton(¹H₂O ) for the imaging of certain regions in the body.

[0036] Nonetheless, certain other magnetically susceptible nuclei aredesired to be adapted for MRI for various reasons. In particular, thephysical characteristics of other elements may predispose the nuclei tothe imaging of other kinds of physical and biological systems. Inmedicine, other nuclei are desired which can enable the imaging ofregions of the body which are difficultly accessible by currentlyavailable NMR probes. Prior to the unexpected observations of theutility of noble gases for MRI applications, as described herein,acceptable alternative nuclear probes have been unavailable.

[0037] Noble gas isotopes having non-zero nuclear spin have now beendiscovered to offer vast possibilities for use in MRI. For example, the¹²⁹Xe isotope is, in principle, suited to NMR uses, but is 26% naturallyabundant and has a sensitivity relative to ¹H (in conventional NMR) of2.12×10^(−2.) The resonance frequency of ¹²⁹Xe spans an enormous range(0-300 ppm) over the gas and condensed phase, and is exceptionallysensitive to chemical environment. (Reference 2). Its longitudinalrelaxation time, T₁, is huge (practically at least 3000 s in the puregas phase, and theoretically perhaps as long as 56 hrs at 1 atm),(References 32, 41), and is particularly sensitive to chemicalenvironment, O₂ concentration, (References 17-18), and the effects ofother relaxation promoters. (References 2, 42, 16). Its transverserelaxation time is also susceptible to relaxation promoters. (References16, 18, 43).

[0038] The longitudinal and transverse relaxation times, T₁ and T₂,respectively, are also indicative of the environment surrounding the¹²⁹Xe atom, e.g., whether the atom is bound to a protein, dissolved in alipid, or constrained in some other way. Thus a combination of chemicalshift, T₁, and T₂ data can provide a basis for distinguishing thepresence or absence of the nucleus in a particular environment as wellas for identifying the nature of the environment in question.

[0039] Elemental Xenon is a benign and effective anesthetic, (Reference44), which is not metabolized by the body. Xenon has an essentiallyRaoult's Law solubility in non-polar solvents. (Reference 45). Inhaledinto the lungs, Xenon equilibrates quickly with the pulmonarycirculation, reaching a steady state with the entire blood volume in oneblood circuit, (Reference 13), on average, about 1 s or 1-2 breaths inthe mouse, about 18 s in humans. (Reference 46). Xenon is known toaccumulate rapidly in highly-vascularized tissue. For example, in thebrain, which contains 10% lipid and 10% protein, (Reference 10), one canexpect steady-state concentrations (for 0.5-1.0 atm lung Xenon) of 5-10mM in the membrane bilayers, 2-4 mM in water, and about 1-5 mM bound toproteins. (References 45, 47-48). Xenon is also approximately twice assoluble in white matter as in gray matter. (Reference 13). The NMRresonance frequency of ¹²⁹Xe is different in each of the above sites,and exchange between compartments is slow on the chemical shift NMRtimescale. (References 2, 16-17). The potential usefulness ofhyperpolarized ¹²⁹Xe as a contrast agent in biological systems istherefore apparent.

[0040] The total Xenon concentration in materials of biological interestwill typically range between about two and about five times itssolubility in pure water. The problem with any attempt to imageBoltzmann polarized Xenon in such a system is that many samples arerequired in order to determine a solution parameter. These difficultiesstem in large part from the lower concentrations of ¹²⁹Xe, its smallermagnetic moment, and its lower natural abundance, as compared with ¹H₂O.Similar considerations apply with regard to other noble gases which aregenerally less soluble in water as well as in non-polar media.

[0041] For example, the spectrum of FIG. 1c, obtained in 8 hrs from invitro brain samples taken from rats anesthetized with Xenon gas, hassignificantly less signal to noise (S/N) than a spectrum of ¹²⁹Xe in asynaptosomal suspension shown in FIG. 1a, obtained in 27 hrs under a Xepressure of 3 atm.

[0042] The difficulties which have heretofore prevented the developmentof noble gas MRI are clear: typically long longitudinal relaxation timesand low signal strength require signal averaging of exceedingly manyfree induction decays (FIDs) over long periods of time. It is clear thatto conduct in vivo NMR experiments, extraordinary enhancement of thenoble gas signal is necessary. The total accumulation times forBoltzmann noble gas spectra is prohibitively long in such biologicalsamples.

[0043] The ability to use noble gases for NMR imaging, then, is directlyand profoundly limited by the average signal intensity and the signalacquisition ability of the spectrometer. Given current NMR spectrometertechnology, it is reasonable to conclude that on the order of a 10,000fold increase in sensitivity, e.g., that increase necessary to renderXenon imaging possible using Boltzmann polarized Xenon, could take yearsif not decades to develop, assuming it is feasible at all. The requiredsensitivity increase is more practicably attained throughhyperpolarization, for example, through the use of optical pumping andspin exchange, (References 21-22, 32, 36), or metastability exchange.(References 26-31). This method of enhancing the noble gas signal can beused to create noble gas nuclear polarizations which are on the order of10⁴-10⁶ larger than typical thermal equilibrium polarizations. Nuclearpolarizations attained using these techniques are easily of order 0.25,(Reference 32), and can approach 1.0, making the product of spin densityand polarization at least an order of magnitude larger than for theproton (¹H) in typical imaging situations. Thus, it has now beenunexpectedly found that the hyperpolarization of noble gases permits aspectacular new means of producing magnetic resonance images.

[0044] While the extraordinary property of hyperpolarizability of noblegases, especially ¹²⁹Xe and ³He, is of great importance in rendering theimaging of biological systems possible, other factors play a role indeveloping such images. For example, noble gases exhibit other unusualproperties, including distinctly different behavior compared to ¹H₂O in(a) cell and tissue compartmentalization; (b) dramaticallytime-dependent distribution; and (c) response of resonance frequency,T₁, and T₂ to environment, O₂ concentration and subcellular exchangekinetics. The combination of hyperpolarizability of noble gases andthese other unusual properties enables the use of noble gases as a newand qualitatively different source of NMR image contrast. For example,as opposed to water protons, ¹²⁹Xe is not omnipresent; its space andtime distribution in the body depends entirely on the anatomy andphysiology of Xenon transport. (Reference 13). This permits its use inmagnetic resonance imaging (MRI) and magnetic resonance spectrometry(MRS) studies of soft-tissue anatomy, physiology (e.g., cerebral bloodflow, cerebral activity) and pathology (e.g., demyelination, earlydetection of tumors or other foci of changed or anomalous metabolism).Moreover, the large MR signal strengths obtainable using hyperpolarizednoble gases permit the use of the high-speed imaging protocols, whichhave heretofore been possible only with ¹H₂O.

[0045] The imaging method of the invention is preferably performed usingthe ¹²⁹Xe and/or the ³He nuclei. However, the method of the inventionmay also be performed with other noble gases, i.e., other noble gasisotopes having nuclear spin. ³He, ¹²⁹Xe and the other noble gases maybe preferred in different applications because of their differentphysical and magnetic resonance properties. A list of noble gas nucleiuseful according to the invention is provided below in Table I. Thislist is intended to be illustrative and non-limiting. TABLE IHyperpolarizable Noble Gases Natural Nuclear Isotope Abundance (%) Spin³He ˜10⁻⁶ 1/2 ²¹Ne 0.27 3/2 ⁸³Kr 11.5 9/2 ¹²⁹Xe 26.4 1/2 ¹³¹Xe 21.2 3/2

[0046] While each of the noble gas isotopes listed in Table I, alone orin combination, may be used for nuclear magnetic resonance imagingaccording to the invention, it is known that the degree of polarizationof the gases in equilibrium (Boltzmann) state is prohibitively low,preventing high speed image acquisition. The various parametersgoverning signal decay such as T₁ and T₂ relaxation and the localenvironment of the nucleus will also determine whether high speed imagescan be effectively acquired. These limitations become of greatimportance in acquisition of images from in vitro and in vivo biologicalsystems since the time course of events desired to be imaged oftenrequires data acquisition periods of less than one second. Enhancementof the NMR signal is, therefore, highly desirable. Accordingly, thenoble gas is preferably hyperpolarized relative to its normal Boltzmannpolarization. Such hyperpolarization is preferably induced prior to dataacquisition by an NMR spectrometer and may be induced by any of thetechniques known in the art.

[0047] Further enhancement of the noble gas magnetic resonance signalmay be obtained, independently of, or together with, hyperpolarization,by increasing the proportion of the imageable isotope in each noble gasto a level above the natural abundance of such imageable isotopes in thenoble gas. In the case of ¹²⁹Xe, which has a natural isotopic abundanceof about 26%, this amounts to enhancement by no more than a factor offour, even in a gas which is enriched to 100% ¹²⁹Xe. Otherconsiderations, such as the hyperpolarizability of the noble gas,usually play a much larger role in signal enhancement, but isotopicenrichment can provide a significant contribution to the ultimateefficacy of the present invention. This is especially true in the caseof ³He which has a natural abundance of on the order of 10⁻⁶. Even thehyperpolarizability of ³He and its very large magnetic resonance signalcould be considerably offset by the low natural abundance of thisisotope. Despite its low natural abundance, however, ³He is readilyavailable in very pure form as a result of industrial use of tritium(³H), which decays exclusively to ³He. The ready availability ofartificial sources of ³He eliminates concerns regarding its low naturalabundance and associated expensive enrichment processes.

[0048] Noble gases may be hyperpolarized for use according to theinvention through any of various means known in the art, such asspin-exchange interactions with optically pumped alkali metal vapor.(References 34-35, 49-50). The optical pumping and spin-exchange can beperformed in the absence of an applied magnetic field, but is preferablyperformed using modest fields of about 1 G or larger. Pumping in the NMRmagnet bore at fields of several Tesla is also possible. The maximumsteady state ¹²⁹Xe nuclear polarization achievable depends on the timeconstant characterizing the spin exchange with the alkali metal and thetime constant characterizing the relaxation (T₁) due, for example, tocontact with the surfaces of the pumping cell. For instance, with T₁≈20min, polarizations of 20-40% are quite practicable, (Reference 32), andpolarizations of 90% or more should be attainable. The long T₁ of thegas also allows samples to be manipulated, even stored as Xe ice,(Reference 32), and transported on time scales of hours or even days,without serious loss of magnetization.

[0049] The art of hyperpolarizing noble gases through spin exchange withan optically pumped alkali-metal vapor starts with the irradiation ofthe alkali-metal vapor with circularly polarized light at the wavelengthof the first principal (D₁) resonance of the alkali metal (e.g. 795 nmfor Rb). The ²S_(1/2) ground state atoms are thus excited to the²P_(1/2) state and subsequently decay back to the ground state. Ifperformed in a modest (10 Gauss) magnetic field aligned along the axisof incident D₁ light, this cycling of atoms between the ground and firstexcited states leads to nearly 100% polarization of the atoms in a fewmicroseconds. This polarization is carried mostly by the lone valenceelectron characteristic of all alkali metals; this essentially meansthat all of these electrons have their spin either aligned oranti-aligned to the magnetic field depending upon the helicity (right-or left-handed circular polarization state) of the pumping light. If anoble gas with non-zero nuclear spin is also present, the alkali-metalatoms can undergo collisions with the noble gas atoms in which thepolarization of the valence electrons is transferred to the noble-gasnuclei through a mutual spin flip. This spin exchange results from theFermi-contact hyperfine interaction between the electron and thenoble-gas nucleus. By maintaining the alkali-metal polarization atnearly 100% with the pumping light, large non-equilibrium polarizations(5%-80%) are currently achievable in large quantities of a variety ofnoble gases through this spin-exchange process. For example, onecurrently available Titanium:Sapphire-laser could theoretically provide1 g/hr (200 cc-atm/hr) of highly polarized ¹²⁹Xe.

[0050] The alkali metals capable of acting as spin exchange partners inoptically pumped systems include any of the alkali metals. Preferredalkali metals for this hyperpolarization technique include Sodium-23,Potassium-39, Rubidium-85, Rubidium-87, and Cesium-133. Alkali metalisotopes, useful according to the invention, and their relativeabundance and nuclear spins are listed in Table II, below. This list isintended to be illustrative and non-limiting. TABLE II Alkali MetalsCapable of Spin Exchange Natural Nuclear Isotope Abundance (%) Spin ²³Na100 3/2 ³⁹K 93.3 3/2 ⁸⁵Rb 72.2 5/2 ⁸⁷Rb 27.8 3/2 ¹³³Cs 100 7/2

[0051] Alternatively, the noble gas may be hyperpolarized usingmetastability exchange. (References 28, 51). The technique ofmetastability exchange involves direct optical pumping of, for example,³He, without need for an alkali metal intermediary. The method ofmetastability exchange usually involves the excitation of ground state³He atoms (1¹S₀) to a metastable state (2³S₁) by weak radio frequencydischarge. The 2³S₁ atoms are then optically pumped using circularlypolarized light having a wavelength of 1.08 μm in the case of ³He. Thelight drives transitions up to the 2³P states, producing highpolarizations in the metastable state to which the 2³P atoms then decay.The polarization of the 2³S₁ states is rapidly transferred to the groundstate through metastability exchange collisions between metastable andground state atoms. Metastability exchange optical pumping will work inthe same low magnetic fields in which spin exchange pumping works.Similar polarizations are achievable, but generally at lower pressures,e.g., about 0-10 Torr.

[0052] The method of the invention preferably includes detecting andimaging at least one physical dimension of the spatial distribution ofat least one noble gas, more preferably including detecting and imagingtwo or three physical dimensions. The method of the invention may alsoinclude detecting and imaging alterations in the spatial distribution ofthe noble gas as a function of time.

[0053] The generating of a representation of a noble gas preferablyincludes generating a representation of at least one physical dimensionof the spatial distribution of the noble gas, more preferably includinggenerating a representation of two or three physical dimensions of thenoble gas. The generating of the representation may also includegenerating a representation of one or more physical dimensions of thespatial distribution of the noble gas as a function of time, includingsuch NMR parameters as chemical shift, T₁ relaxation, T₂ relaxation andT_(1ρ)relaxation. Preferably, the method of the invention includesgenerating a visual representation.

[0054] Representations of the spatial distribution of a noble gas may begenerated by any of the methods known in the art, subject to the type ofinformation desired to be represented. These techniques employ variousmeans for collecting and manipulating nuclear magnetic resonance datafor the generation of images. Such methods are described in theliterature available in the art and include, without limitation, Fourierimaging, planar imaging, echo planar imaging, projection-reconstructionimaging, spin-warp Fourier imaging, gradient recalled acquisition in thesteady state (GRASS) imaging also known as fast low angle shot (FLASH)imaging, and hybrid imaging.

[0055] Such imaging methods are described in, for example, Ernst et al.,Principles of Nuclear Magnetic Resonance in One and Two Dimensions(1987) (Reference 52), particularly Chapter 10, “Nuclear MagneticResonance Imaging”, pages 539-564; Shaw, D. D., “The FundamentalPrinciples of Nuclear Magnetic Resonance”, Chapter 1 in BiomedicalMagnetic Resonance Imaging, S. W. Wehrli et al. eds. (1988) (Reference53); and Stark et al. eds., Magnetic Resonance Imaging, Vol. 1, 2d ed.(1992) (Reference 40). These publications are incorporated herein byreference.

[0056] The selection of imaging method will depend on the behavior ofthe noble gas nucleus under investigation, the nature of the sample andthe degree of interaction of the nucleus with the sample. The selectionof imaging method will also depend on whether one or more spatialdimensions of the spatial distribution of the noble gas is desired to berepresented and whether a temporal or time-dependent dimension isdesired to be represented. When a multidimensional representation isdesired such representation may be generated by, for example,multi-slice imaging or volume imaging.

[0057] It is generally preferred that the image or representation begenerated by a method which is as fast and as sensitive as possible.Preferred imaging methods include the FLASH or GRASS imaging method andthe echo-planar imaging (EPI) method. These methods are preferred fortheir capacity to generate images through fast data acquisition, therebyconserving polarization of the noble gas. EPI is especially preferredbecause it is a relatively fast method and requires only oneradio-frequency (RF) pulse per image. It thus permits maximumutilization of the available polarization. These preferred methods alsopermit fast time resolution of time-dependent phenomena in human andanimal subjects. Such applications include, for example, magneticresonance angiography (MRA) studies, functional imaging of the nervoussystem (e.g., brain), as well as studies of variations incardiopulmonary and circulatory physiological states.

[0058] The nuclear magnetic resonance imaging method of the inventionalso includes the registration of multiple imaging modalities. Forexample, using coils tunable to ¹²⁹Xe frequencies and the frequencies ofone or more other magnetic probes permits enhanced data interpretation.Such combined multiple imaging approaches would include, for example thecombined imaging of ¹²⁹Xe with ¹H, and the imaging of more than onenoble gas, such as imaging of ¹²⁹Xe with ³He. In this embodiment,geometric image registry and overlay are possible, including thegeneration of false-color images, in which distinct colors wouldrepresent distinct probes. Image subtraction techniques would also bepossible using combinations of ¹²⁹Xe with other probes, or combinationsof noble gas probes.

[0059] The noble gas being imaged is preferably distributed spatially inat least one physical phase such as a gas, liquid, gel, or solid. Thenoble gas may be imaged as distributed in two or more physical phases inone sample. The noble gas being imaged may be distributed on a solidsurface. The noble gas may be imaged in association with variousmaterials or environments such as, without limitation, zeolites, xenonclathrates, xenon hydrates, and polymers.

[0060] The sample being imaged using a noble gas may include an in vitrochemical, in vitro biological or in vivo biological, system. When thenoble gas distribution in an in vivo biological system is imaged, thesystem may include one or more human or animal subjects. The noble gasis preferably distributed in an organ or body system of the human oranimal subject, including, without limitation, lung tissue, nervoustissue, brain tissue, gastrointestinal tissue or cardiovascular tissueor combinations thereof. Alternatively, the noble gas may be distributedin an anatomical space such as, without limitation, lung space,gastrointestinal tract space, peritoneal space, bladder space orcombinations thereof.

[0061] The noble gas may be contacted with the sample to be imaged ingaseous or liquid form, either alone or in combination with othercomponents in a gaseous or liquid composition. The noble gas may becombined with other noble gases and/or other inert or active components.The noble gas may be delivered as one or more boluses or by continuousor quasi-continuous delivery.

[0062] In a preferred embodiment, there is also provided a method ofperforming nuclear magnetic resonance imaging of an animal or humansubject by administering an imageable amount of a hyperpolarized noblegas to the subject, employing an NMR spectrometer to generate and detectradio-frequency signals derived from the magnetic resonance of the noblegas, processing the detected signals to obtain an NMR parameter data setas a function of the spatial distribution of the noble gas, and furtherprocessing the data set to generate a representation corresponding to atleast one dimension of the spatial distribution of the noble gas.

[0063] The noble gas may be administered to a human or animal subject asa gas or as a liquid, either alone or in combination with other noblegases and/or other inert or active components. The noble gas may beadministered as a gas by either passive or active inhalation or bydirect injection into an anatomical space such as lung orgastrointestinal tract. The noble gas may be administered as a liquid byenteral or parenteral injection. The preferred method of parenteraladministration includes intravenous administration, optionally bycontacting blood with the noble gas extracorporeally and reintroducingthe noble gas-contacted blood by intravenous means.

[0064] The cost of a purified noble gas tends to be relatively high ascompared to the cost of common gases such as nitrogen or carbon dioxide.The cost is especially high in the case of Xenon which has been enrichedto, for example, 70% ¹²⁹Xe. However, being inert, the noble gas is notmetabolized in biological systems and can be recovered. For example,Xenon can be recovered from the exhaled breath of human subjects overabout a 20 minute period. Such apparatus for noble gas recovery andrepurification would include, for example, a cold trap and/or azirconium getter apparatus, such as are known in the art. Otherapparatus for recovery of noble gases may be employed.

[0065] It is preferred that, because of the high cost of the noble gas,the gas be maintained in a system which is substantially sealed toprevent loss to the atmosphere. Sealed containment apparatus wouldinclude a noble gas source, such as a gas canister or compressed gastank, conduits to and away from a sample, as well as recovery apparatus.

[0066] The noble gas source may include a permanent or semi-permanentcanister or pressurized containment apparatus. Alternatively, the noblegas may be supplied in disposable or refillable one-use containers suchas pressurized gas ampoules or cylinders. The noble gas source may beintegrated with a sealed noble gas supply and recovery system or may bestored separately and affixed to and opened to the supply and recoverysystem on a periodic or as-needed basis.

[0067] The sample to be studied, whether a physical structure, achemical system, an in vitro system, a living animal or human host, orother suitable sample, is preferably imaged using apparatus whichsubstantially prevents loss of Xenon to the environment, although theinvention may be practiced without such apparatus. Thus, a sample may beimaged while maintained in a sample chamber substantially suffused orsuffusable with the noble gas. Alternatively, for human or animalsubjects, the subject may be fitted with an administration device, suchas a sealed mask, for administration of the noble gas. In such cases,the sample chamber or noble gas administration device preferablycommunicates with a noble gas source and/or a noble gas recoveryapparatus.

[0068] A hyperpolarized noble gas may be stored for extended periods oftime in a hyperpolarized state. Storage systems capable of cryogenicstorage of a hyperpolarized noble gas are preferably able to maintaintemperatures such that noble gas is stored in frozen state. Frozen ¹²⁹Xecan be reasonably maintained at fields of ≧500 Gauss at temperaturesranging from 4.2 K (liquid helium temperature), for which T₁ is about amillion seconds (10 days), to 77 K (liquid nitrogen temperature), forwhich T₁ is about 10 thousand seconds. The fields necessary here may beprovided by a small permanent magnet or by a larger electromagnettypically carrying on the order of ten or more amperes of current. For³He, things are quite different. Relaxation rates are such that low10-20 Gauss fields can be used to hold it at room temperature-a fewatmospheres will live for days under these conditions. The field herecould also be a permanent magnet or a Helmholtz pair of coils carryingabout one ampere of current. The conditions required for maintainingother hyperpolarized noble gases may be determined by those skilled inthe art.

[0069] A noble gas which has been hyperpolarized by spin exchange withan alkali metal may be stored either before or after removal of anyalkali metal used in spin exchange hyperpolarization techniques. In allcases in which rubidium or other alkali metal would interfere with thebehavior of the system the alkali metal is removed before introductionof the noble gas to the sample. This removal of toxic alkali metal isimportant in biological samples and is especially critical in cases inwhich the sample is a living human or animal subject.

[0070] An alkali metal removal device may be employed either distantfrom the imaging site or proximally thereto. For example, the alkalimetal removal device may be incorporated in a sealed noble gasadministration system at a point prior to a conduit to a sample chamberor other administration device.

[0071] An alkali metal removal device would generally include a conduitfor conducting the noble gas to a region or chamber which is cooler thanthe pumping region. At room temperature, the saturated vapor pressure ofRubidium, i.e., the pressure in an enclosure in the presence of a poolof liquid Rubidium, is about 10⁻⁹ atm. By moving the noble gas away fromany macroscopic pools of liquid Rubidium, any remaining vapor is likelyto plate out onto a cool (e.g., room temperature) surface, thereby neverreaching an experimental subject. It is preferred, however, that a coldtrap, such as is known in the art, be used.

[0072] The delivery of the noble gas to a sample may be performed assingle or multiple bolus delivery. Such delivery would ordinarily besuited to the study of systems in which observations of the change innoble gas distribution is important. Such systems would include, interalia, human or animal subjects in which an anatomical or physiologicalevent or events are being examined as a function of time. Alternatively,the delivery of the noble gas to a sample may be performed as acontinuous or quasi-continuous delivery. Such delivery would ordinarilybe desired when steady state analyses of samples are desired. Forexample, high resolution imaging of human or animal organ systems wouldbe possible by sequential imaging of steady state Xenon concentrationsby data processing, e.g., image subtraction or signal averaging.Hyperpolarized Xenon or other noble gas could also be used as a markeror for contrast enhancement in whole body ¹H₂O NMR imaging in which thenoble gas NMR signal could be digitally subtracted from the ¹H₂O NMRimage. For example, hyperpolarized Xenon could be introduced in thegastrointestinal tract of a subject to inflate the regions therein andto provide contrast enhancement when digital subtraction of signals isperformed.

[0073] Comparative data have been obtained which illustrate the NMRbehavior of ¹²⁹Xe in various environments. For example, various groupshave determined chemical shift and relaxation rates (T₁ and T₂) for¹²⁹Xe in environments such as n-octanol, benzene, water and myoglobin.(See References 2, 16). Octanol represents a relatively non-polarlipid-like environment resembling the interior of the cell membrane,water models aqueous regions, and the myoglobin solution represents aprotein to which Xenon is known to bind. (Reference 54). The measuredrange of resonance frequencies for Xenon extends approximately 300 ppmover the gas and condensed phase. (Reference 2). Although the range ofchemical shifts observed in these model biological systems is not aslarge as that in other solvents, it is large compared to the relevant¹⁹F brain resonance values that have been reported. (Reference 3).

[0074] Moreover, the huge range of T₁ values is extraordinary. Table IIIlists some reported values of T₁ and T₂ for ¹²⁹Xe in octanol, water andaqueous Fe(III) metmyoglobin (Reference 54); models representing twomajor cell compartments, lipid membrane and cytosol. The values for T₁in octanol, 80 s, and water, 130 s, provide an indication of theextraordinarily long lifetimes of ¹²⁹Xe polarization (anoxic tissue withno other relaxers). In other biological environments, longer T₁ valuesare possible. The lower limit is unknown: The 5 ms T₁ in 10% Fe(III)metMb (a strong relaxer) implies a physiological lower limit much higherthan this. The extremely short T₁ and T₂ values found for the proteinsolution certainly occur because Xenon binds very near the paramagneticcenter of metmyoglobin. (Reference 54). TABLE III ENVIRONMENT T₁(s)T₂(s) Δ¹²⁹Xe (ppm)* Octanol 78.5 5.3 204.6 Water 131.3 5.3 195.3Myoglobin 5.2 × 10⁻³ 0.57 × 10⁻³ 199.4 Benzene 160.5 0.88 196.4 Pure GasPhase 56 hrs ≦56 hrs 0.4 (1 atm)

[0075] The value of T₁ in benzene at 300°K, i.e., T₁=160 s, agrees wellwith that of Diehl and Jokisaari, i.e., T₁=155.0±6.2 s, at 9.4 T and300°K, (Reference 43), rather than with the value of T₁=240 s obtainedby Moschos and Reisse. (Reference 55). Measurements of T₁ and T₂ for¹²⁹Xe are difficult to obtain, hence scarce. The values quoted hererepresent a significant fraction of the known list. The difficulties areobvious: typically, longitudinal relaxation times are long; low signalstrength requires signal averaging of many free induction decay (FID)traces, hence very long overall accumulation times. The problem isparticularly acute in aqueous systems: as noted above, the solubility ofXenon at 30°C., 0.5 atm, is 48 mM in octanol, but only 2.4 mM in water.

[0076] It would be desirable to investigate the possibility of observingmultiple ¹²⁹Xe resonances within brain tissue, but the small signal fromthe small, largely aqueous brain volume of a live mouse, breathing anatmosphere of 50-70% normal Boltzmann-polarization ¹²⁹Xe, would requirean enormous time interval of data collection for adequate signalaveraging.

[0077] Seeking a system that would be tolerably stable for the necessarytime interval, capable of being sealed with Xenon at 2-3 atm, but closeenough to functioning brain cells, the behavior of Xenon in asynaptosome suspension has been studied. (Reference 16). Synaptosomesare presynaptic nerve terminals sheared away from their attachments toform resealed subcellular pseudocells that retain the morphology andchemical composition of the terminal nerve cell region, and much of themembrane functionality. Synaptosomes are rich in postsynaptic adhesionsand constitute a source for postsynaptic membranes, synaptosomalmitochondria, transmitter receptors, and cleft material.

[0078]FIG. 1a shows a smooth, high S/N spectrum of 3 atm Xenon inequilibrium over a 10% (wet weight) rat brain synaptosome suspension asdescribed by Albert et al. (Reference 16). This spectrum isresolution-enhanced with Gaussian broadening of 0.01 Hz and linebroadening of −5.0 Hz. Two peaks can be seen; a broad resonance of about3.4 ppm to higher frequency of a narrow component. The narrow peakappeared 0.33 ppm to higher frequency of that of ¹²⁹Xe in pure water,and is likely due to bulk magnetic susceptibility shift effects.Although collected using a simple one-pulse sequence, the spectrumrequired 27 hours of signal averaging to obtain the degree of signalstrength and resolution shown.

[0079] An alternative model for investigating ¹²⁹Xe behavior in braintissue has also been tested. FIG. 1b shows a ¹²⁹Xe spectrum obtainedfrom a sample of rat brain homogenate as described by Albert et al. (SeeReference 16). This spectrum also shows two resolved peaks; indicatingthat slow-exchange compartmentalization of ¹²⁹Xe in complex biologicalsystems can also be observed. The decrease in high-field signal (aqueous¹²⁹Xe) as compared to the synaptosomal spectrum (FIG. 1a) reflects adecrease in water content in the preparation. The spectrum of FIG. 1brequired 8 hours of data accumulation, reflecting the difficultiesinherent in attempting to examine ¹²⁹Xe in biological systems.

[0080] The behavior of ¹²⁹Xe in brain tissue has been studied byinvestigating whether any signal could be obtained from ¹²⁹Xe in wholerat brains. (See Reference 16). FIG. 1c shows a spectrum of ¹²⁹Xeobtained from a whole rat brain preparation, again showing two resolvedpeaks, but obtained with further decreased S/N. The two resolved peaksprovide further evidence that ¹²⁹Xe is slow-exchange compartmentalizedin complex biological systems. A further decrease in the proportion ofhigh-field signal (aqueous ¹²⁹Xe) as compared to FIGS. 1a and 1 b,reflects a further decrease in water content in this sample preparation.The spectrum required 8 hours of data accumulation, again illustratingthe difficulty of obtaining NMR data from ¹²⁹Xe in biological systems.

[0081] It is known that ¹²⁹Xe, which has a long longitudinal relaxationtime in the gas phase, can be relaxed by magnetic dipole-dipoleinteraction and/or Fermi-Contact interaction with the unpaired electronspins of dioxygen. (Reference 18). The solubility of Xenon (and also ofdioxygen) in water is low. Due to the low sensitivity of the ¹²⁹Xesignal, the time required for determining the relaxivity of O₂ toward¹²⁹Xe with a series of T₁ determinations over a range of O₂concentrations in water would be prohibitively long.

[0082] The relaxivity of O₂ toward ¹²⁹Xe has been measured in only oneliquid, i.e., octanol, which models an amphipathic membrane lipid.(Reference 17). The observed relaxivity, 0.029 s⁻¹mM⁻¹, is about threetimes larger than that estimated from previous reports for gas-phaserelaxation, i.e., (Reference 18), 0.0087 s⁻¹mM⁻¹, as might be expectedfor encounters in the condensed phase. The dioxygen relaxivity for ¹²⁹Xeis constant over the concentration range studied, and thus 1/T₁ will bea linear function of O₂ concentration over the entire physiologicalrange (0-0.2 atm, 0-0.2 mM). This translates into a T₁ value of 18 s inair-saturated lipid, and 80 s in anaerobic lipid, in the absence ofother relaxers. This is the first reported value for the O₂ relaxivitytoward ¹²⁹Xe in a condensed phase. T₂values over these O₂ concentrationshave been determined to range from 0.5 to 5.0 s. These results indicatethat the range of T₁ to be expected in tissue in vivo is about 1-20 s.In fact, given the relative inefficiency of the known non-paramagneticrelaxation mechanisms, it is suspected that T₁ in many tissues will notfall below seconds or even tens of seconds. These results are ofcritical importance to physiological studies using ¹²⁹Xe magneticresonance spectroscopy.

[0083] Using Boltzmann polarization ¹²⁹Xe, data have been obtained whichallow estimation of T₁=38 s (±8 s, SD) for ¹²⁹Xe dissolved in rat bloodat 293°K. (Reference 17). However, since 12 hours were required toobtain this data set, the result serves only to estimate what the normalphysiological T₁ might be in vivo.

[0084] This estimate of T₁≈38 s for ¹²⁹Xe dissolved in rat blood at293°K is very encouraging. Although this result, obtained over a 12 hrperiod (using Boltzmann ¹²⁹Xe), might not be representative ofphysiological blood, the changes likely to occur in blood maintained atroom temperature for long periods, e.g., methemoglobin formation, wouldtend to decrease the value observed for T₁. One can also estimate T₁values for other model systems. The T₁ of ¹²⁹Xe in water has beenmeasured at 300°K to be 130 s. (Reference 16). ¹²⁹Xe exchange withprotein binding sites will lower this value, (Reference 16), but thecontribution from aqueous O₂ should be minimal. T₁ for ¹²⁹Xe in octanol,a classic membrane phase model, is 80 s. (References 16-17). Sincemembrane bilayers sequester both Xe and O₂, it should be possible to usethe values for Xenon and Oxygen distribution ratios, (Reference 45),between octanol and water of 20:1 and 6:1, respectively, and of the O₂relaxivity in octanol of 0.029 s⁻¹mM⁻¹ at 300°K, (Reference 17), toestimate the T₁ value for ¹²⁹Xe in fully oxygenated membranes to be >15s. While the actual values of T₁ in each tissue must be, and remain tobe, determined, it is expected that the minimum value will fall above 15s, a duration sufficient to enable significant accumulation of polarized¹²⁹Xe in major tissues.

[0085] The unusual and extraordinary properties of hyperpolarized noblegases permit imaging of a wide variety of organs, body systems, andanatomical structures. Such structures can be imaged in live or deceasedsubjects, depending on application, and such subjects can include humanas well as animal subjects. For example, hyperpolarized Xenon will haveparticular clinical importance in providing nuclear magnetic resonanceimaging of neural tissue diseases, vascular plaques, compromised bloodflow, tumors, as well as functional imaging of the brain's response tosensory stimuli. The properties of other noble gases will render themuseful in a variety of other situations. For example, it is expectedthat because of its low solubility, ³He will be of major clinicalimportance in imaging anatomical spaces such as lung or otherartificially inflated organs.

[0086] The differential solubility of Xenon and other lipid soluble,hyperpolarizable noble gas isotopes would permit noble gas NMRdifferentiation between white and gray matter in brain tissue, whilelipid membranes are essentially invisible to ¹H₂O MRI. For example, withrespect to neural tissue disease, in white matter regions of the lowermedulla and the spinal cord ¹H₂O MRI contrast is poor, while the highlipid solubility of Xenon and other noble gas anesthetics will permitimaging of hyperpolarized isotopes. Such imaging would have diagnosticimportance for patients suffering from nerve tissue demyelination.Hyperpolarized noble gas MRI would be of use for imaging of subduralhematomas as well as cystic and necrotic changes. Indications of lownoble gas uptake in avascular regions would be valuable in demonstratingisodense fluid collections. (Reference 56). With respect todifferentiation between tumors and infarcts, in ischemic lesions, noblegas washin/washout is delayed and blood flow is diminished, while ininfarcted tissue, only the noble gas equilibrium level is diminished. Incases of multiple sclerosis, ¹H₂O MRI often cannot provide useful imagesof plaques, while differential noble gas uptake (high in normal tissuevs. low in demyelinated plaques) would permit effective Xenon images.Similarly, in cerebral vascular and peripheral blood vessel plaques, theplaques have little or no noble gas uptake and would appear dark in anoble gas image. (Reference 57).

[0087] Images of Xenon (and other noble gas anesthetics) would alsoindicate cerebral, coronary and peripheral vessel defects; providingobvious indications of blood vessel constrictions and aneurysms. Inparticular, measurements of regional cerebral blood flow would bepossible with greater exactness than is possible with other techniques.Also, study of the effects of spasms on blood flow in cases ofsubarachnoid hemorrhage would be rendered possible.

[0088] Functional study of brain tissue is also expected to bedramatically enhanced by the imaging of hyperpolarized noble gasanesthetics, especially Xenon, according to the invention. For example,changes in local blood flow caused by visual, tactile, and other stimulishould produce dramatic fluctuations in ¹²⁹Xe signal intensity. Inaddition, the elucidation of the precise relationships betweenneurological changes and psychological states has been a major goal ofneurobiologists. Electroencephalography, positron emission tomography(PET), and recently, ¹H₂O MRI, have been used in this field.Hyperpolarized Xenon MRI, with its high sensitivity, as exploitedthrough fast electronics, has the potential to make huge contributionsto this area. Disease states such as epilepsy, schizophrenia, depressionand bipolar illness can be studied.

[0089] Clearly, hyperpolarized noble gas MRI has essentially unlimitedpotential application in medical settings. Hyperpolarized noble gas MRIcould displace or supplement conventional MRI, and even the ubiquitousbut intrusive X-ray CT scan, in at least several large areas: (1) thelung, heart, and cardiovascular systems; (2) the brain, especially sincebrain membrane lipids are invisible using current techniques; (3) brainfunction, since the ¹²⁹Xe signal will respond directly and strongly tometabolic changes in neural tissue.

[0090] Noble gas MRI promises to complement ¹H₂O -based imaging in adramatic way. The near million-fold enhancement in sensitivity to noblegases enabled by hyperpolarization should result in temporal and spatialresolution in imaging superior to that achievable with ¹H₂. In addition,the solubility of, for example, Xenon in lipids should permit imaging oforgans that currently require far more intrusive techniques such asX-ray computerized tomography scanning.

[0091] The following non-limiting Examples are intended to furtherillustrate the present invention. In the Examples provided below, theexperimental conditions were as follows unless otherwise noted: magneticresonance spectra were obtained using a Bruker MSL 400 spectrometerequipped with a 9.4 T widebore vertical magnet, an ASPECT 3000 computer,a BVT 1000 variable temperature control unit, and employing ahigh-gradient Bruker micro-imaging probe and solenoidal transceivercoils of 13.3 and 20 mm diameter, operating at 110.7 MHz for ¹²⁹Xe and400 MHz for ¹H. The spectrometer was not field frequency locked duringthe image acquisitions.

EXAMPLE 1

[0092] Xenon-Oxygen and Xenon-Oxygen-octanol “Boltzmann” imagingphantoms were prepared by standard quantitative high-vacuum gas-transfertechniques. Xenon gas, enriched to 70% ¹²⁹Xe, was obtained from IsotecInc., of Miamisburg, Ohio.

[0093] Image acquisition made use of a Fast-Low-Angle-SHot (FLASH) phaserefocused, free-precession, fast gradient-echo imaging sequence asdescribed by Haase et al. (Reference 58). This sampling-pulse techniquewas originally introduced by Look et al. (Reference 59). Standard protonmicroimaging gradients of 100 mT/m yielded a 50×50 mm² field of view for¹²⁹Xe. A 128×64 encoding matrix was used, which set the spatialresolution to 0.8×0.8×8 mm³.

[0094]FIG. 2b illustrates an image of a 20 mm ¹²⁹Xe glass phantomcontaining 5 atm Xe at Boltzmann equilibrium polarization (2 atm O₂ wasused to reduce T₁). This image may be compared to those images in FIGS.3c and 3 d. FIG. 3 illustrates the spectrum and images of a ¹²⁹Xegas-octanol glass phantom containing ca. 5 atm Xe at Boltzmannequilibrium polarization (2 atm O₂ was used to reduce T₁). The observedresolution of 1×2×20 mm³ per volumetric picture element (voxel) wasachieved by accumulating 64 replicate FLASH imaging sequences over 7min. Note that, as shown in FIG. 3b, the ¹²⁹Xe signals from the gas andoctanol phases are separated by 186 ppm: this implies that the imaginggradients produce no overlap.

EXAMPLE 2

[0095] Images of hyperpolarized ¹²⁹Xe in glass sphere phantoms wereobtained as follows. Optical pumping cells were constructed of 13-18 mmdiameter Pyrex® spheres. Before filling, the cells were coated with asiliconizing agent Surfasil obtained from Pierce, of Rockford, Ill.,attached to a high vacuum manifold, evacuated to ˜10⁻⁸ Torr, and bakedat 150°C. for about 24 hours. The silicone coating apparently reducesrelaxation of ¹²⁹Xe on the walls of the glass sphere, permittingcreation of larger polarizations. The spheres were then filled with400-1800 Torr Xe, 75 Torr N₂ and a few milligrams of Rubidium metal.Once filled with the test gas or gas/liquid, the glass cells were flamesealed.

[0096] Optical polarization was performed generally in accordance withtechniques known in the art, in particular the methods of Cates et al.,(Reference 35), as follows. The cells were heated to 85° C. The entirevolume of the cell was exposed to 2-4 W of 795 nm Rb D₁ laser light froma Spectra Physics 3900S Titanium-Sapphire laser, which was itself pumpedby a Spectra Physics 171 Argon-Ion laser operating at 18-23 W. Bothlasers were obtained from Spectra Physics of Mountain View, Calif. Thelaser illumination of the cells was performed in the bore of the 9.4 Tmagnet described above, at a field strength of 9.4 T. After 15-20 min.of optical pumping, the cells were cooled to room temperature andemployed for MR experiments.

[0097] Image acquisition made use of a Fast-Low-Angle-SHot (FLASH) phaserefocused, free-precession, fast gradient-echo imaging sequence asdescribed by Haase et al. (Reference 49). This sampling-pulse techniquewas originally introduced by Look et al. (Reference 50). This techniquetakes advantage of the fact that, for small θ, the transverseprojection, i.e., sin θ, allows substantial signal strength, while theloss in longitudinal projection, i.e., 1-cos θ, permits only a smallloss in Z-magnetization per pulse. Standard proton microimaginggradients of 100 mT/m yielded a 50×50 mm² field of view for ¹²⁹Xe. A128×128 encoding matrix was used, which set the spatial resolution to0.37×0.37×1 mm³.

[0098]FIG. 4 illustrates a series of images obtained from slices in theplane defined by the Y and Z axes through a 13 mm diameter cellcontaining 400 Torr of laser-polarized Xenon. The laser-polarization wasperformed within the bore of the 9.4 T magnet. Each image was collectedin a single FLASH sequence lasting 600 msec., with 0.37×0.37×1 mm³resolution. FIG. 4d displays the variation in ¹²⁹Xe intensitycharacteristic of an image slice through a domed end of the sphere. Theother slices were obtained from sections closer to the center of thespherical phantom and are more homogeneous and uniformly bright. Forthis experiment the ¹²⁹Xe polarization was estimated to be 25-30% bysignal comparison to a cell of identical dimensions containing Xenon ata higher pressure but at Boltzmann polarization (illustrated in FIG.3b).

EXAMPLE 3

[0099] Nuclear magnetic resonance images of mouse lungs were obtainedusing hyperpolarized ¹²⁹Xe according to the following method.

[0100] In order to deliver a quantity of hyperpolarized ¹²⁹Xe to abiological specimen, several obstacles must be overcome. To date, ¹²⁹Xehas only been successfully hyperpolarized in very pristine environmentssuch as sealed glass cells. Such purity is essential because anyparamagnetic impurities will greatly reduce the longitudinal relaxationtime T₁ of the gas and thus lower the achievable polarizations. Topreserve the successful sealed-cell polarization techniques and stilldeliver the polarized gas to an external specimen, cells equipped withthin break seals were developed. A glass delivery tube, equipped with apiston, was devised so that, once the ¹²⁹Xe was polarized, the cellscould be sealed into the delivery tube, their break seals broken by theaction of the piston, and the polarized gas freed to expand into thebiological specimen.

[0101]FIG. 7 shows a delivery tube device 10 developed for the deliveryof a noble gas, e.g., ¹²⁹Xe, from a sealed cell 16 to a sample withinthe bore of an NMR spectrometer. The delivery device 10 includes acylinder 12 within which a piston 14 can be controllably displaced in anaxial direction. The cylinder 12 is threaded on an external surface atone end. The cylinder threads match threads on the internal surface of acontrol handle 22 which is rotatably attached to the piston 14. Thedevice also includes at least one O-ring 24, 26 providing a gas tightseal between the internal surface of the piston 14, while permittingaxial movement of the piston relative to the cylinder. At the other endof the cylinder 12, i.e., opposite the threads adapted for receiving thecontrol handle 22, is sealable inlet port 20 adapted for receiving abreakable neck 18 of the sealed cell 16 containing pressurized noblegas. The inlet port 20 is sealed with a glass-sealing wax around thebreakable neck 18 of the sealed cell 16 containing pressurized noblegas. The delivery device 10 also includes an outlet 28 communicatingwith the inlet port 20 connected to a conduit 30 to a medical sample andthrough which a noble gas can be delivered to the sample. The deadvolume 32 in the delivery device is preferably as small as possible tominimize dilution of the noble gas as it passes from the cell 16 to themedical sample during operation of the delivery device 10. The O-rings24 are therefore also preferably positioned as close to the break pointof the sealed neck 18 as possible.

[0102] The device 10 is preferably operated in situ, i.e., inside theNMR spectrometer used for imaging the noble gas in the sample, and isdesigned so that the seal of cell 16 can be broken by remotemanipulation of the control handle 22, which when rotated displaces thepiston 14 toward the neck 16 until contact with neck 16 is madesufficient to break neck 16 and release the pressurized noble gas.

[0103] Mouse lungs, intact with trachea and heart were freshly excisedfrom 30-35 g Swiss-Webster mice which had been freshly euthanized with100 mg/kg sodium pentobarbital. The trachea was intubated with 1 mm ODSilastic medical grade tubing and the heart-lung preparation was placedin a 10 mm internal diameter glass cylinder, inserted into a 13.3 mmimaging coil and flushed with one inflation of N₂. Polarized Xenon gaswas prepared as described in Example 2 except that the cells wereilluminated away the bore of the 9.4 T magnet at a low field strength(approximately 10 mT). The hyperpolarized ¹²⁹Xe was delivered throughthe use of 18 mm OD Pyrex spheres provided with break-seal stems whichhad been sealed into a vacuum tight glass delivery tube (illustrated inFIG. 7) suspended in the bore of the magnet. The tubing from the mousetrachea was attached to the end of the delivery tube. Once thebreak-seal had been fractured, the 13-20 atm/cm³ Xenon was free toexpand into the lung. Gas pressures and volumes were adjusted to inflatethe lung to approximately 1 atm of gas within one second, during whichtime only a minimal amount of relaxation of the polarization could takeplace.

[0104] Images were obtained using the NMR protocol described in Example2 above. FIG. 5 presents a sequence of images illustrating thetime-evolution (t=0-10 s) of the distribution of hyperpolarized ¹²⁹Xeentering the lung of a heart preparation. The images represent 1.0 mmthick slices through mouse lung inflated with laser-polarized ¹²⁹Xe gas.The plane of the slices is perpendicular to the (absent) vertebralcolumn (i.e., anatomical cross section). Voxel size is 0.37×0.37×1 mm³,and specimen diameter is 10 mm.

[0105]FIG. 5a shows a ¹²⁹Xe image of lung obtained immediately afterinflation (i.e., t=0 s), such that the lung is completely expanded tofill the glass cylindrical enclosure. At this point, the lung stilllargely contains the N₂ from the dead volume of the delivery system.Only the trachea, hints of the bronchi, and some of the lung peripheryhave received ¹²⁹Xe at this point.

[0106]FIG. 5b is an image obtained about 1 s later than the image inFIG. 5a (i.e., t=1 s). At this time the maximally inflated lung hasreceived substantial ¹²⁹Xe. Both lobes of the lung can be seen withsignificant contrast variation and a small darker central region wherethe heart excludes the Xenon gas. Note that the lobes of the lung haveexpanded to press against the interior surface of the 10 mm diameterglass tube in which they are contained.

[0107]FIG. 5c is an image obtained seven seconds later than the imageobtained in FIG. 5b, (i.e., t=8 s), showing that the lung has partiallydeflated. The lobes are more clearly delineated and the central heartspace is more apparent. The y-axis resolution of this image is lowerbecause it was anticipated, incorrectly, that the ¹²⁹Xe magnetizationremaining after the image in FIG. 5b would necessitate the use of largervoxels and fewer slice selection pulses. Thus not all imaging parameterswere optimized in acquiring these images. Optimization would likely haveproduce resolution between 2 and 4 times better than that achieved.

[0108] Finally, FIG. 5d shows a ¹H image of the same slice of theheart-lung preparation. The heart, just below center, is the primarysource of intensity, while a drop of saline delineates the upper leftboundary, as confirmed by visual observation of the sample.

[0109] Thus, the ¹²⁹Xe lung image is an excellent complement to standardproton NMR imaging. The ¹²⁹Xe image is clearly bright where the ¹H imageis dark, and vice versa. Lung tissue is not readily seen in water protonimages; only at magnified intensity does one see a faint trace of thelobes. It is believed that this phenomenon is not the result of arelative lack of protons, but is almost certainly due to the extremelocal variation in bulk magnetic susceptibility at the highly complexgas-tissue interface which causes extremely short T₂ values. (SeeReference 8). This is, evidently, not a problem for gas phase ¹²⁹Xe.

[0110]FIG. 6 shows the time variation of ¹²⁹Xe magnetization in the samelung as that imaged in FIG. 5 after another bolus of hyperpolarized¹²⁹Xe. The decrease in ¹²⁹Xe magnetization following the rapid influx of¹²⁹Xe into the lung is distinctly not monoexponential. The curve,decomposed into a sum of two exponentials, allows a value of T₁ ofapproximately 28 s to be extracted from the trailing edge of the decay.The early decrease in intensity probably reflects bulk transfer of ¹²⁹Xeout of the lung (deflation to resting volume) rather than magnetizationdecay. This is evident from the difference between the turgid lung inFIG. 5b (ca. 1 s after Xe release) and the lung in FIG. 5c (7 s later):the lobes have shrunk and the bright trachea has descended. This effectwas confirmed visually using boli of N₂.

[0111] The ¹²⁹Xe images shown in FIG. 5 were obtained in 600 ms using aXenon concentration of approximately 40 mM, a concentration which istiny compared to the 80-100 M concentrations of proton typical of ¹H₂Oimaging. Nonetheless, the signal intensities, spatial resolution (<0.3mm³), and data acquisition rates all exceed those obtained inconventional clinical ¹H₂O-MRI. Moreover, the magnetization densitiesare so large that several images can be generated in rapid succession,allowing for real-time tracking of physiological processes.

[0112] It is believed that these images are the first reported foreither Boltzmann or laser polarized ¹²⁹Xe. While FIG. 5 demonstratesquite clearly the power of this technique for imaging the lungs, it mayturn out that ³He, which has a larger magnetic moment, longer gas phaseT₁ values, (References 60-61), and which is significantly less expensivethan ¹²⁹Xe, may be the nucleus of choice for lung imaging. However, thefeatures of Xenon which are unmatched by the lighter noble gases,include its good solubility in non-polar solvents and its highelectronic polarizability, (Reference 47), which is responsible for theextreme sensitivity of the ¹²⁹Xe resonance frequency and relaxation timevalues to environment. (References 16-17).

[0113] Such applications, however, do require that the longitudinalrelaxation time of polarized ¹²⁹Xe be long compared to the time scalesof the processes being studied. The question that immediately arises iswhether the T₁ of polarized ¹²⁹Xe in the lung is long enough to permittransport of sufficient magnetized probe to the various tissues, andwhether T₁ in these tissues will allow survival of adequate signal forimaging.

[0114] While long relaxation times can be attained by laboriouslyconstructing pristine environments such as pumping cells (T₁>30 min),biological situations pose a marked departure from such idealconditions. For instance, as noted above, paramagnetic O₂ in the gasphase has been shown to relax ¹²⁹Xe with a relaxivity of 0.0087 s⁻¹mM⁻¹.(Reference 18). Measurements showing that T₁≈28 s in the nitrogenflushed lung indicate that this is quite sufficient for lung imagingapplications. This is demonstrated by the fact that two images, 7seconds apart, could be acquired with a single bolus of Xenon. For thecase of a live, breathing animal, we can use the O₂ relaxivity data toestimate the contribution to relaxation for the component of Oxygencontained in alveolar air (˜110 Torr, 5.7 mM). For an animal breathing40-75% Xenon and 20% O₂, we estimate T₁ to be on the order of 10-15 s,which is clearly adequate for lung imaging (FIG. 9.3 c). Moreover, 12 srepresents 5-10 blood circuits in a mouse, (Reference 62), and nearly afull circuit in a human. (Reference 63). Pulmonary blood should receiveadequate concentrations of polarized ¹²⁹Xe.

[0115] The high ¹²⁹Xe polarizations attained permit the use ofhigh-speed imaging protocols hitherto limited to ¹H₂O. We note that ourfield gradients and acquisition programs, conservatively chosen to matchstandard 1H₂O protocols, waste both time and ¹²⁹Xe magnetizationsampling empty voxels. Without any optimization of parameters, thecontrast and resolution are already quite adequate. Future optimizationof imaging parameters should easily improve upon these early images.Moreover, typical voxel sizes for human specimens, especially under themore exigent restraints of functional imaging, are 3×3×8 mm³, or larger.(Reference 64). This represents a voxel that is 500 times larger thanthose displayed in FIG. 5. This represents, of course, either 500 foldmore ¹²⁹Xe spins per voxel or the feasibility of 500 fold dilution ofthe ¹²⁹Xe for equivalent signal intensity.

[0116] Though our studies made use of relatively expensive isotopicallyenriched Xenon (70% ¹²⁹Xe), a sacrifice of a factor of only 3 in MRsignal would result from the use of inexpensive natural abundance Xenon(26% ¹²⁹Xe). Because the polarizations achieved through opticaltechniques are entirely field-independent, (References 32, 20), MRsignals scale only linearly with field. Thus, MRI using laser-polarizedgases can be performed at lower magnetic fields with only linearsacrifices in signal intensity (as opposed to the quadratic loss withBoltzmann polarization MR). In fact, the ratio of hyperpolarized toBoltzmann spin excess increases as magnetic field decreases; thus, in a1 T clinical magnet the ratio is 10⁶.

[0117] If the actual relaxation times in different physiologicalenvironments turn out to be close to those estimated above, theextension of ¹²⁹Xe imaging to other parts of the body should prove to belimitless.

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[0182] While there have been described what are presently believed to bethe preferred embodiments of the invention, those skilled in the artwill realize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention, and it is intended to claimall such changes and modifications as fall within the true scope of theinvention.

We claim:
 1. A method of nuclear magnetic resonance (NMR) imaging, whichcomprises the steps of: a) detecting a spatial distribution of a noblegas by NMR; and b) generating a representation of said spatialdistribution of said noble gas.
 2. The method of claim 1 , wherein saidnoble gas is selected from the group consisting of Helium-3, Neon-21,Krypton-83, Xenon-129, Xenon-131, and mixtures thereof.
 3. The method ofclaim 2 , wherein said at least one noble gas includes Xenon-129.
 4. Themethod of claim 2 , wherein said noble gas includes Helium-3.
 5. Themethod of claim 2 wherein said noble gas includes Xenon-129 andHelium-3.
 6. The method of claim 1 , further comprising the step ofhyperpolarizing said noble gas prior to said detecting step.
 7. Themethod of claim 6 , wherein said hyperpolarizing step compriseshyperpolarizing said noble gas through spin exchange with an alkalimetal.
 8. The method of claim 6 , wherein said hyperpolarizing stepcomprises hyperpolarizing said noble gas through metastability exchange.9. The method of claim 7 , wherein said alkali metal is selected fromthe group consisting of Sodium-23, Potassium-39, Cesium-133,Rubidium-85, and Rubidium-87.
 10. The method of claim 9 , wherein saidalkali metal is selected from the group comprising Rubidium-85 andRubidium-87.
 11. The method of claim 1 , wherein said detecting stepfurther comprises detecting said spatial distribution of said noble gasalong at least one physical dimension.
 12. The method of claim 11 ,wherein said detecting step further comprises detecting said spatialdistribution of said noble gas along two physical dimensions.
 13. Themethod of claim 11 , wherein said detecting step further comprisesdetecting said spatial distribution of said noble gas along threephysical dimensions.
 14. The method of claim 1 , wherein saidrepresentation comprises a visual representation.
 15. The method ofclaim 1 , wherein said detecting step precedes said generating step. 16.The method of claim 1 , wherein said detecting step and said generatingstep are substantially simultaneous.
 17. The method of claim 1 , whereinsaid generating step includes generating said representation from NMRparametric data.
 18. The method of claim 17 , wherein said NMRparametric data includes data computationally derived from at least onephysically measurable NMR parameter selected from the group consistingof chemical shift, T₁ relaxation, T₂ relaxation, and T_(1ρ)relaxation.19. The method of claim 1 , wherein said at least one noble gas isdistributed in at least one physical phase.
 20. The method of claim 19 ,wherein said at least one noble gas is distributed in a gas.
 21. Themethod of claim 19 , wherein said at least one noble gas is distributedin a liquid.
 22. The method of claim 19 , wherein said at least onenoble gas is distributed in a solid.
 23. The method of claim 22 ,wherein said at least one noble gas is distributed in a solid surface.24. The method of claim 19 , wherein said at least one noble gas isdistributed in at least two physical phases.
 25. The method of claim 1 ,wherein said at least one noble gas is distributed in an in vitrochemical system.
 26. The method of claim 1 , wherein said at least onenoble gas is distributed in an in vitro biological system.
 27. Themethod of claim 1 , wherein said noble gas is distributed in a human oranimal subject.
 28. The method of claim 27 , wherein said noble gas isdistributed in an organ or body system of said human or animal subject.29. The method of claim 28 , wherein said noble gas is distributed inlung tissue of said human or animal subject.
 30. The method of claim 28, wherein said noble gas is distributed in nervous tissue of said humanor animal subject.
 31. The method of claim 30 , wherein said noble gasis distributed in brain tissue of said human or animal subject.
 32. Themethod of claim 27 , wherein said noble gas is distributed in ananatomical space of said human or animal subject.
 33. The method ofclaim 32 , wherein said anatomical space comprises lung space.
 34. Themethod of claim 32 , wherein said anatomical space comprisesgastrointestinal tract space.
 35. The method of claim 1 , furthercomprising administering said noble gas to a human or animal subject.36. The method of claim 35 , wherein said noble gas administering stepcomprises administering said noble gas in a gaseous form.
 37. The methodof claim 36 , wherein said noble gas administering step comprisesadministering said noble gas to said human or animal subject by passiveor active inhalation.
 38. The method of claim 35 , wherein said noblegas administering step comprises administering said noble gas to saidhuman or animal subject included in a liquid composition.
 39. The methodof claim 38 , wherein said noble gas administering step comprisesadministering said noble gas by parenteral injection.
 40. The method ofclaim 39 , wherein said noble gas administering step comprisesadministering said noble gas by intravenous injection.
 41. The method ofclaim 40 , wherein said noble gas administering step further comprisesintroducing said noble gas into blood and intravenously injecting thenoble gas-containing blood into said human or animal subject.
 42. Themethod of claim 1 , wherein said representation represents at least onespatial dimension of said noble gas spatial distribution.
 43. The methodof claim 42 , wherein said representation represents two spatialdimensions of said noble gas spatial distribution.
 44. The method ofclaim 42 , wherein said representation represents three spatialdimension of said noble gas spatial distribution.
 45. The method ofclaim 42 , wherein said representation further represents at least onespatial dimension of said noble gas spatial distribution as a functionof time.
 46. Apparatus for nuclear magnetic resonance imaging, whichcomprises: a) means for imaging a spatial distribution of ahyperpolarized noble gas by NMR ; and b) means for providing imageablequantities of said hyperpolarized noble gas to a sample to be imaged bysaid imaging means.
 47. The apparatus of claim 46 , wherein saidproviding means further comprises means for hyperpolarizing said noblegas to generate a hyperpolarized noble gas.
 48. The apparatus of claim47 , wherein said hyperpolarizing means includes means forhyperpolarizing said noble gas by spin exchange with an alkali metal.49. The apparatus of claim 47 , wherein said hyperpolarizing meansincludes means for hyperpolarizing said noble gas by metastabilityexchange.
 50. The apparatus of claim 42 , wherein said providing meansfurther comprises means for storing said at least one hyperpolarizednoble gas.
 51. A medical composition, comprising a medically acceptablebifunctional gas effective for concurrent in vivo anesthesiological andmagnetic resonance imaging functions.
 52. The medical composition ofclaim 51 , wherein said bifunctional gas comprises at least onehyperpolarized noble gas.
 53. The medical composition of claim 51 ,wherein said bifunctional gas further comprises a medically acceptablecarrier gas.
 54. A method of performing nuclear magnetic resonance (NMR)imaging of a human or animal subject, which comprises the steps of: a)administering to said subject an imageable amount of a hyperpolarizednoble gas; b) generating radio frequency signals from the hyperpolarizednoble gas by means of a nuclear magnetic resonance imaging spectrometer;c) detecting radio-frequency signals derived from nuclear magneticresonance of the hyperpolarized noble gas; d) processing said radiofrequency signals to provide an NMR parameter data set as a function ofspatial distribution of the hyperpolarized noble gas; and e) furtherprocessing the NMR parameter data set to derive a representationcorresponding to at least one spatial dimension of the spatialdistribution of the hyperpolarized noble gas.
 55. The method of claim 54, wherein said administering step further comprises administering a gascomposition to said subject.
 56. The method of claim 55 , wherein saidadministering step further comprises passive or active inhalation ofsaid gas composition by said subject.
 57. The method of claim 55 ,wherein said administering step further comprises administering saidnoble gas as at least one bolus.
 58. The method of claim 55 , whereinsaid administering step further comprises administering said noble gascontinuously during the generating and detecting steps.